3-(n-methyl-n-alkyl)-amino 2-methoxymethylene propan 1-ol derivatives, a preparation process of the same and therapeutical compositions containing them

ABSTRACT

The invention relates to 3-(N-methyl-N-alkyl)-amino 2-methoxymethylene propan 1-ol derivatives of the formula ##STR1## wherein R stands for an alkyl chain, A stands for: ##STR2## and Y represents various quaternary ammonia, to a preparation process of said compounds and to therapeutic compositions containing the same.

The present invention relates to new phospholipid derivatives and, moreparticularly, to new 3-(N-methyl-N-alkyl)-amino 2-methoxymethylenepropan 1-ol derivatives. These new phospholipid compounds are of thefollowing formula: ##STR3## wherein: R stands for an alkyl chain of from10 to 20 carbon atoms;

A stands for: ##STR4## n being an integer of from 2 to 10; Y representsthe following quaternary ammonia: ammonium, alkylammonium,dialkylammonium, trialkylammonium, pyridinium, piperidinium, pyrroliumor pyrrolidinium, each alkyl group having from 1 to 6 carbon atoms,

and therapeutically acceptable salts thereof.

The compounds are more particularly interesting for their anti-tumoractivity, which has been found to be far more important than closelyrelated compounds of the state of the art such as, for instance, thosedescribed in "Synthesis of Thioether Phosphocholine Analogues" (EimarBOSIES, Dieter B. J. HERRMANN, Uwe BICKER, Rudi GALL and Wulf PAHIKE -LIPIDS. Vol 22. No. 11, 1987, p. 947-951).

The invention relates, also, to a preparation process of the compoundsof the general formula I, said process comprising reacting, in anaprotic solvent, in presence of triethylamine, at a temperature of from0° to 80° C., under nitrogen circulation, the compound ##STR5## whereinR is as above defined, on a stoichiometric excess of from 10 to 100% ofa compound selected from within ##STR6## or O═C═N(CH₂)_(n) Br (n beingas above defined), and on a stoichiometric excess of from 30 to 50% of acompound Z, selected from an amine associated with the above definedquaternary ammonia of the formula Y, namely ammoniac, N-alkyl-amine,N,N-dialkylamine, N,N,N-trialkylamine, pyridine, piperidine, pyrrole orpyrrolidine. Of course, in some cases, the reactant Z may be also thesolvent of the reaction. So, the definition "a stoichiometric excess" ismeaningless.

The process may be illustrated by the following reaction scheme I.##STR7##

The invention relates, finally, to therapeutical compositions containingone of the compounds I as an active ingredient therein, in associationwith appropriate diluents and/or carriers.

The starting material II may be prepared as summarized in the followingreaction scheme II and described in detail in the following preparativeexamples 1 to 9 wherein R stands for C₁₂ H₂₅, C₁₆ H₃₃ and C₁₈ H₃₇.

PREPARATIVE EXAMPLES 1. Diethyl 2-phenyl 1,3-dioxane 5,5-dicarboxylate 1

A mixture of diethyl bis-(hydroxymethyl)-malonate (27 gr, 0.12 mole),freshly distilled benzaldehyde (12.5 ml, 0.12 mole) and p-toluenesulfonic acid (0.2 gr) in 250 ml of dry toluene was refluxed for 3 hoursusing a Dean Stark apparatus. The toluene was eliminated in vacuo andthe residue was distilled.

E₀.5 : 170° C. (29.5 gr, yield 78%)

Molecular weight=308

IR: 1 740 cm⁻¹ (C═O)

¹ HNMR 60 MHz CDCl₃, TMS

δ: 7.35 (s, 5H, φ); 5.4 (s, 1H, CHφ); 4.8 (d, 2H); 4.2 (m, 6H, 2H+OCH₂CH₃); 1.2 (m, 6H, OCH₂ CH₃)

2. 5-ethoxycarbonyl 2-phenyl 1,3-dioxane 5-carboxylic acid 2

25 gr of 1 (0.08 mol) were added to a solution of 6.6 gr of KOH (0.11mol) in 140 ml ethanol. After stirring for 4 hours at room temperature,the ethanol was evaporated and the residue was treated with HCl 1N (125ml) at 0° C. The precipitate was filtered off, washed and dried.##STR8##

21.6 gr of 2 were obtained (95%). mp 108° C.

Molecular weight=280

IR (cm⁻¹): 3400 (OH); 3100-3040 (φ); 1740 (COOEt); 1690 (COOH); 1100(C--O--)

¹ HNMR 60 MHz; CDCl₃, TMS.

δ: 7.4 (s, 5H, φ); 5.5 (s, 1H, CHφ); 4.9 (d, 2H, CH₂); 4.25 (m, 4H, 2Hand OCH₂ CH₃); 1.3 (t, 3H, OCH₂ CH₃)

3. Ethyl 2-phenyl 1,3-dioxane 5-carboxylate 3

9.2 gr (0.033 mol) of 2 in 20 ml dry-pyridine were refluxed for 5 hours.Pyridine was eliminated in vacuo, the residue was dissolved in CH₂ Cl₂,washed with water, then with brine, dried and evaporated, to give 3 (6.8gr, 88%) mp 69° C.

Molecular weight=236

IR: 1 740 cm⁻¹ (C═O)

¹ HNMR, 60 MHz, CDCl₃, TMS δ: 7.4 (s, 5H, φ); 5.4 (d, 1H, CHφ); 3.8-4.8(m, 6H); 3.2 (m, 1H, H--C--CO₂ Et); 1.3 (m, 3H, OCH₂ CH₃).

4. 5-hydroxymethylene 2-phenyl 1,3-dioxane 4

To a mixture of 0.62 gr of LiAlH₄ (0.016 mol) in absolute diethyl-ether(80 ml), was added, slowly, a solution of 6.8 g of 3 (0.029 mol) in 60ml of absolute diethylether. The mixture was stirred for 4 hours at roomtemperature. Then, at 0° C., ethyl acetate (8 ml), water (4 ml) and NaOH15% (4 ml) were added. The ethereal layer was decanted, dried andevaporated to afford 5.12 gr (92%) of 4, as a yellow oil. Molecularweight=194

TLC rf: 0.5 (CH₂ Cl₂) on alumina.

IR: 3430 cm⁻¹ (OH)

¹ HNMR 60 MHz, CDCl₃, TMS δ: 7.4 (s, 5H, φ); 5.3 (d, 1H, CHφ); 4.3-3.2(m, 6H); 2.2 (m, 1H, CH--CH₂ OH); 1.3 (1H, OH)

5. 5-methoxymethylene 2-phenyl 1,3-dioxane 5

To a mixture of HNa (50%, 1.06 gr) in 40 ml of dry THF, stirred at 0°C., a solution of 5.12 gr of 4 in 40 ml THF was added dropwise. After 30min, CH₃ I (6.6 ml) was added and the mixture was stirred at 0° C. for 6hours, then overnight at room temperature. Water was added and themixture was extracted with diethyl-ether, the organic layer was washedwith water until neutral, then with brine, dried and evaporated. Theresidue was purified on alumina column (eluent CH₂ Cl₂) to yield 4.8 grof 5 (86%).

Molecular weight=208

TLC rf: 0.86 (CH₂ Cl₂) alumina.

IR (cm⁻¹): 3100-3040 (φ), 1100 (C--O--)

HNMR, 60 MHz, CDCl₃, TMS

δ: 7.4 (s, 5H, φ); 5.5 (d, 1H, H--C--φ); 4.8-3.2 (m, 9H); 2.3 (m, 1H,CH--CH₂ OMe).

6. 2-methoxymethylene 1-0-benzyl propan 1,3-diol 6

To 5 (5.4 gr, 0.026 mol) stirred at 0° C., a solution of BH₃ in THF (M,52 ml) was added dropwise. The mixture was stirred at room temperaturefor 48 hours, then was quenched with cold water at 0° C. and extractedwith diethylether. After elimination of the solvent, the crude productwas chromatographed on silicagel (eluent CH₂ Cl₂ then CH₂ Cl₂ /MeOH99:1) to give 6 (4 gr, 73%) as a viscous oil.

Molecular weight=210

TLC rf: 0.24 (CH₂ Cl₂), alumina

IR (cm⁻¹) 3450 (OH); 3100-3040 (φ); 1100 (C--O--)

¹ HNMR 60 MHz, CDCl₃, TMS δ: 7.3 (s, 5H, φ); 4.5 (s, 2H, CH₂ φ); 3.1-3.7(m, 10 H); 2.1 (m, 1H, CH--CH₂ O--); 2.6 (1H, OH)

7. 3-0. methylsulfonyl, 2-methoxymethylene 1-0 benzyl propan 1,3-diol 7

To a solution of 6 (4 gr, 0.019 mol), in a mixture of 60 ml of drydiethyl ether and 40 ml of dry CH₂ Cl₂, was added, dropwise, ClSO₂ Me(2.24 ml; 0.029 mol). The mixture was stirred at room temperature for 24hours. After extraction with CH₂ Cl₂, the organic layer was washed withbrine till pH 7 and dried. The solvent was evaporated and the residuewas chromatographed on silicagel (eluent CH₂ Cl₂ /MeOH 99:1) to give 7(4.6 g, 84%) as viscous oil.

Molecular weight=288

TLC rf: 0.7 (CH₂ Cl₂ /MeOH: 95:5) silicagel

IR (cm⁻¹): 1350 (SO₂); 1170 (SO₂); 1100 (C--O--C)

¹ HRMN 60 MHz, CDCl₃, TMS (δ) 4.35 (d, 2H, CH₂ OSO₂); 3.3-3.6 (m, 7H);3.0 (s, 3H, SO₂ CH₃); 2.3 (m, 1H, CH--CH₂ O).

The different N,N-(methyl alkyl) amines, except N,N-(octadecylmethyl)amine (Aldrich) were obtained from the corresponding alkyl halideand methyl amine according to I. G. Farbening A. G. Fr. 784,599, Jul.22, 1935.

8. 1-N,N-(methyl alkyl)amino 2-methoxymethylene 3-0-benzyloxy propane 8

7 (0.016 mol) dissolved in DMSO (15 ml) was added to a solution ofN,N-(methyl alkyl)amine (0.016 mol) and Et₃ N (1.4 ml) in DMSO (60 ml).The mixture was stirred at 80° C. for 24 hours. After elimination ofDMSO under reduced pressure, the residue was dissolved in CH₂ Cl₂, theorganic phase was washed with water and dried. The crude product waschromatographed (eluent CH₂ Cl₂ /MeOH 98:2) to give 8.

8a R=C₁₂ H₂₅ (yield 50%--viscous oil) TLC rf: 0.16 (CH₂ Cl₂ /MeOH 95:5)

8b R=C₁₆ H₃₃ (yield 61%--viscous oil) TLC rf: 0.18 (CH₂ Cl₂ /MeOH 95:5)

8c R=C₁₈ H₃₇ (yield 58%--viscous oil) TLC rf: 0.18 (CH₂ Cl₂ /MeOH 95:5)

IR: 1100 (C--O--) cm⁻¹

¹ HNMR 60 MHz, CDCl₃, TMS δ: 7.3 (s, 5H, φ); 4.5 (s, 2H, CH₂ φ); 3.3-3.6(m, 7H, OCH₃, 2CH₂ O); 2.15-2.4 (m, 7H, ##STR9## 1.8 (m, 1H, CH--CH₂ O);1.25 large sing. 2nH, NCH₂ (CH₂)_(n) CH₃ ; 0.9 (t, 3H, CH₃)

9. 3-N,N-(methyl alkyl)amino 2-methoxymethylene propan 1-ol 9

Obtained by hydrogenolysis of 8 in CHCl₃ with Pd/C 10% (40 psi, 5 hoursat 40° C.).

9a R=C₁₂ H₂₅ (yield 79%) TLC rf: 0.36 (CH₂ Cl₂ /MeOH 90:10)

9b R=C₁₆ H₃₃ (yield 87%) TLC rf: 0.39 (CH₂ Cl₂ /MeOH 90:10)

9c R=C₁₈ H₃₇ (yield 85%) TLC rf: 0.39 (CH₂ Cl₂ /MeOH 90:10) Molecularweight=385

IR (cm⁻¹): 3450 (OH) ; 1100 (C--O--C)

¹ HNMR, 60 MHz, CDCl₃, TMS δ: 5.3 (1H, OH); 3.3-3.8 (m, 7H, OCH₃, 2 CH₂O) 2.7 (m, 7H, NCH₃ and CH₂ --N--CH₂); 2.2 (m, 1H, CH--CH₂ O); 1.25large sing, 2nH, NCH₂ (CH₂)_(n) CH₃ ; 0.9 (t, 3H, CH₃)

The invention will be better understood from the description of thefollowing examples.

EXAMPLE 10 3-N,N-(methyl alkyl)amino 2-methoxymethylene propan 1-0phosphocholine

Alkyl stands for --C₁₂ H₂₅, --C₁₆ H₃₃ and --C₁₈ H₃₇ ##STR10## Y=--N⁺(CH₃)₃

To a cooled (5° C.), stirred solution of 9 (7 mmol) and 3 ml of NEt₃ indry benzene (20 ml), was added 2-chloro 2-oxo 1,3,2-dioxaphospholane (2gr, 14 mmol) in 4 ml of C₆ H₆, under nitrogen circulation. The mixturewas stirred at room temperature for 8 hours, then filtered. The filtratewas evaporated off under reduced pressure. The residue was dissolved indry CH₃ CN (50 ml) and transferred in a reactor. 30 ml of CH₃ CNsaturated by gaseous NMe₃ were added and the mixture was heated at 65°C. for 24 hours. The solvent was evaporated and the residue waschromatographed on silicagel (eluent CHCl₃ /MeOH 90:10; 70:30; 30:70then MeOH) to yield the title compound.

10a R=C₁₂ H₂₅ (yield 40%) MH⁺ =467 TLC rf: 0.25 (CHCl₃ /MeOH/NH₄ OH70:30:7)

10b R=C₁₆ H₃₃ (yield 44%) MH⁺ =523 TLC rf: 0.26 (CHCl₃ /MeOH/NH₄ OH70:30:7)

10c R=C₁₈ H₃₇ (yield 45%) MH⁺ =551 TLC rf: 0.26 (CHCl₃ /MeOH/NH₄ OH70:30:7)

IR (cm⁻¹): 1240 (P═O); 1100 (C--O--C); 1040 (P--O)

¹ HNMR, 500 MHz, CH₃ OD, TMS δ: 0.85 (t, 3H, CH₃); 1.2 [large sing, 2nH,(CH₂)_(n) ]; 1.45 (m, 2H, NCH₂ CH₂); 2.0 (m, 1H, CH--CH₂ O); 2.15 (s,3H, NCH₃); 2.3 (m, 4H, CH₂ --N--CH₂); 3.15 [s, 9H, N (CH₃)₃ ]; 3.35 (s,3H, OCH₃); 3.4 (d, 2H, CH₂ --OCH₃); 3.55 (m, 2H, CH₂ N⁺); 3.85 (m, 2H,CH₂ OP); 4.25 (m, 2H, POCH₂).

EXAMPLE 11 3-N,N-(methyl alkyl)amino 2-methoxymethylene1-[6'-(N-pyridinium)pentylcarboxy] propane bromide

Alkyl stands for --C₁₂ H₂₅, --C₁₆ H₃₃ and --C₁₈ H₃₇ ##STR11##

A solution of 9 (9 mmol) and triethylamine (25 mmol) in 15 ml ofethanol-free trichloromethane, were added dropwise to a solution of 10mmol of 5-bromohexanoyl chloride in 10 ml of the same solvent at 0° C.under nitrogen circulation. The mixture was then stirred for about 15hours at room temperature. After evaporation of solvent, 30 ml of drypyridine was added to the obtained residue, and the mixture was thenstirred at 80° C. under nitrogen circulation for 24 hours. Pyridine waseliminated in vacuo and the residue was purified by columnchromatography (eluent CHCl₃, then CHCl₃ /MeOH 90:10) to yield the titlecompound.

11a R=C₁₂ H₂₅ (yield 68%)

11b R=C₁₆ H₃₃ (yield 60%)

11c R=C₁₈ H₃₇ (yield 71%)

IR (cm⁻¹): 1100 (C--O--C); 1740 (C═O); 1640 (pyridine)

¹ HNMR, 500 MHz, CDCl₃, TMS δ: 0.85 (t, 3H, CH₃); 1.2 [large sing, 2nH,(CH₂)n]; 2.2 (s, 3H, NCH₃); 2.35 [t, 2H, C(O)CH₂ ]; 3.35 (s, 3H, OCH₃);3.45 (d, 2H, CH₂ --OCH₃)

EXAMPLE 12 3-N,N-(methyl alkyl)amino 2-methoxymethylene1-[6'-(N-pyridinium) pentylcarbamoyloxy] propane bromide

Alkyl stands for --C₁₂ H₂₅, --C₁₆ H₃₃ and --C₁₈ H₃₇ ##STR12##

A mixture of 9 (9 mmol), 5-bromopentylisocyanate (12 mmol) in benzeneand 30 ml of pyridine, was heated for two days at 80° C. under nitrogencirculation. Pyridine was eliminated in vacuo and the obtained residuewas dissolved in CHCl₃, washed and dried. The solvent was evaporated andthe residue was chromatographed (CHCl₃ then CHCl₃ /MeOH, 95:5, 90:10) togive the title compound.

12a R=C₁₂ H₂₅ (yield 49%)

12b R=C₁₆ H₂₃ (yield 52%)

12c R=C₁₈ H₃₇ (yield 62%)

IR (cm⁻¹): 1100 (C--O--C); 1640 (pyridine) 1720 (CONH); 3350 (NH)

¹ HNMR, 500 MHz, CDCl₃, TMS δ: 0.90 (t, 3H, CH₃); 1.2 [large sing, 2nH,(CH₂)_(n) ]; 2.15 (s, 3H, NCH₃); 3.25 [t, 2H, C(O)NHCH₂ ]; 3.35 (s, 3H,OCH₃); 3.4 (d, 2H, CH₂ --OCH₃); 5.1 (t, 2H, CH₂ N⁺); 5.6 (d, 1H, NH)

EXAMPLE 13 3-N,N-(methyl alkyl)amino 2-methoxymethylene1-[6'-(N-piperidinium)pentylcarbamoyloxy]propane bromide

Alkyl stands for --C₁₂ H₃₅, --C₁₆ H₃₃ and --C₁₈ H₃₇ ##STR13##

This compound is prepared by the same process as described in example12, but using piperidine instead of pyridine.

13a R=C₁₂ H₂₅ (yield 49%)

13b R=C₁₆ H₃₃ (yield 42%)

13c R=C₁₈ H₃₇ (yield 53%)

IR (cm⁻¹): 1100 (C--O--C); 1720 (CONH); 3350 (NH)

¹ HNMR, 500 MHz, CDCl₃, TMS δ: 0.85 (t, 3H, CH₃); 1.2 [large sing, 2nH,(CH₂)n]; 2.15 (s, 3H, NCH₃); 3.25 [t, 2H, C(O)NHCH₂ ]; 3.35 (s, 3H,OCH₃); 3.4 (d, 2H, CH₂ --O--CH₃); 5 (t, 2H, CH₂ N⁺); 5.6 (d, 1H, NH)

EXAMPLE 14 3-N,N-(methyl alkyl)amino 2-methoxymethylene1-[6'-(N-pyrrolium) pentylcarbamoyloxy]propane bromide

Alkyl stands for --C₁₂ H₃₅, --C₁₆ H₃₃ and --C₁₈ H₃₇ ##STR14##

This compound is prepared by the same process as described in example12, but using pyrrole instead of pyridine.

14a R=C₁₂ H₂₅ (yield 53%)

14b R=C₁₆ H₃₃ (yield 61%)

14c R=C₁₈ H₃₇ (yield 48%)

IR(cm⁻¹) 1100 C--O--C); 1720 (CONH); 3350 (NH)

¹ HNMR, 500 MHz, CDCl₃, TMS δ: 0.85 (t, 3H, CH₃); 1.2 [large sing, 2nH,(CH₂)n]; 2.2 (s, 3H, NCH₃); 3.25 [t, 2H, C(O)NHCH₂ ]; 3.35 (s, 3H,OCH₃); 3.4 (d, 2H, CH₂ --O--CH₃); 5 (t, 2H, CH₂ N⁺); 5.6 (d, 1H, NH)

EXAMPLE 15 3-N,N-(methyl alkyl)amino 2-methoxymethylene1-[6'-(N-pyrrolidinium)pentylcarbamoyloxy]propane bromide

Alkyl stands for --C₁₆ H₃₃, --C₁₇ H₃₅ and --C₁₈ H₃₇ ##STR15##

This compound is prepared by the same procedure as described in example12, but using pyrrolidine instead of pyridine.

15a R=C₁₂ H₂₅ (yield 49%)

15b R=C₁₆ H₃₃ (yield 45%)

15c R=C₁₈ H₃₇ (yield 56%)

IR(cm⁻¹): 1100 (C--O--C); 1720 (CONH); 3350 (NH)

¹ HNMR, 500 MHz, CDCl₃, TMS δ: 0.85 (t, 3H, CH₃); 1.2 [large sing, 2nH,(CH₂)n]; 2.15 (s, 3H, NCH₃); 3.25 [t, 2H, C(O)NHCH₂ ; 3.35 (s, 3H,OCH₃); 3.4 (d, 2H, CH₂ --O--CH₃); 5 (t, 2H, CH₂ N⁺); 5.6 (d, 1H, NH)

Toxicity

The toxicity of the compounds of the invention, has been determined peros on mice, by usual methods. Their LD₅₀ values are higher than 650mg/kg.

Pharmacology

The compounds of the invention have been examined for their ability toinhibit in vitro tumor cell proliferation.

They inhibit HL60 and A.427 tumor cell proliferation after 24 hours.

HL60: promyelocytic leukemia cell line

A.427: lung carcinoma cell line

They show a cytostatic effect at the dose of 0.02 mM which is not atoxic dose for the two human tumor cell lines. Overall, the lungcarcinoma cell line resulted more sensitive than the promyelocyticleukemia cell line.

The effect of the compounds of the invention on long-term proliferationhas been more precisely described above.

All of the examples of the invention have been tested and compared withone of the first related compounds discovered as inhibiting theneoplastic cell-growth: the 1-0-octadecyl-2-0-methylglycero-3-phosphocholine (ET180CH₃ or methoxy PAF; Andreesen, 1988).

For this study, a lung carcinoma cell line, called A.427, have beenused; they are anchorage-dependent cells.

The A.427 cells were grown in EMEM medium containing sodium pyruvate andnon-essential amino acids (Flow Labs), supplemented with 10% foetalbovine serum (FBS; Gibco). The growth media contained 100 U/ml ofpenicillin and 100 μg/ml of streptomycin (Flow Labs).

The compounds of the invention and the reference compound ET180CH₃(Bachem; Switzerland) were dissolved in a solution containing 60%ethanol and 40% phosphate buffer saline (PBS; Flow Labs). Serialdilutions were prepared in PBS. The dose tested was 0.02 mM. Thetreatment time lasted 24 hours at 37° C.

The effect of the compounds of the invention on long-term cellproliferation and survival has been evaluated by studying the platingefficiency and colony morphology of A.427. To carry out this study,1.10³ A.427 cells, previously treated with the compounds of theinvention for 24 hours, were seeded into 25 cm² growth area tissueculture flasks.

These cell cultures were then incubated at 37° C. for 15 days. At theend of this incubation time, the cell cultures were rinsed twice withPBS, fixed with 70% ethanol for 30 minutes and stained for the samelength of time with 10% Giemsa (Sigma Chemicals).

The results are expressed as `relative plating efficiency (P.E.)` valuescalculated as follows: ##EQU1## and summarized in the following table.

It has been found that the colonies formed after treatment of compoundsof the invention have lost their regular profile, have a lowerreactivity to the Giemsa stain and, overall, have a size which issmaller than that of the untreated colonies.

    ______________________________________                                        COMPOUNDS      P.E. (%)                                                       ______________________________________                                        Control        100 ±     2.2                                               ET18OCH3       33.4 ±    1.5                                               EX 10-a        27.1 ±    2.6**                                             EX 10-b        21.4 ±    1.8*                                              EX 10-c        14.2 ±    0.9***                                            EX 11-a        23.2 ±    2.4*                                              EX 11-b        18.5 ±    2.1*                                              EX 12-a        25.6 ±    3.1**                                             EX 12-b        20.2 ±    2.3**                                             EX 13-b        19.1 ±    3.6***                                            EX 13-c        17.6 ±    2.7*                                              EX 14-a        22.7 ±    3.1*                                              EX 14-b        27.3 ±    3.3*                                              EX 14-c        18.6 ±    2.7**                                             EX 15-b        21.7 ±    3.3**                                             EX 15-c        26.4 ±    2.6**                                             ______________________________________                                    

The statistical symbols refer to the comparison between each examplewith the reference ET180CH₃. The different symbols: NS, *, ** and ***mean that the result is respectively not significative, significative,very significative and highly significative.

Posology

In human therapy, the compounds of the invention are preferablyadministrated by I.V. route. Usual posology is from 2.5 to 5 mg/dm² perdiem, three to six days per months in slow perfusion.

We claim:
 1. 3-(N-methyl-N-alkyl)-amino 2-methoxymethylene propan 1-olderivatives of the general formula: ##STR16## wherein: R stands for analkyl chain of from 10 to 20 carbon atoms;A stands for: ##STR17## nbeing an integer of from 2 to 10; Y represents the following quaternaryammonia: ammonium, alkylammonium, dialkylammonium, trialkylammonium,pyridinium, piperidinium, pyrrolium or pyrrolidinium, each alkyl grouphaving from 1 to 6 carbon atoms,and therapeutically acceptable saltsthereof.
 2. Therapeutic compositions containing an effective amount ofat least one compound according claim 1, as an active ingredient,associated with appropriate diluents and/or carriers for the selectedadministration route.